Processes for Preparing 3-Benzazepines

ABSTRACT

The present invention provides processes and intermediates for the preparation of 3-benzazepines and salts thereof which can be useful as serotonin (5-HT) receptor agonists for the treatment of, for example, central nervous system disorders such as obesity.

FIELD OF THE INVENTION

The present invention generally relates to processes and intermediatesfor the preparation of 3-benzazepines and salts thereof which can beuseful as serotonin (5-HT) receptor agonists for the treatment of, forexample, central nervous system disorders such as obesity.

BACKGROUND OF THE INVENTION

Serotonin (5-HT) neurotransmission plays an important role in numerousphysiological processes both in health and in psychiatric disorders. Forexample, 5-HT has been implicated in the regulation of feeding behavior.5-HT is believed to work by inducing a feeling of fullness or satiety soeating stops earlier and fewer calories are consumed. It has been shownthat a stimulatory action of 5-HT on the 5HT_(2C) receptor plays animportant role in the control of eating and in the anti-obesity effectof d-fenfluramine. As the 5-HT_(2C) receptor is expressed in highdensity in the brain (notably in the limbic structures, extrapyramidalpathways, thalamus and hypothalamus i.e. PVN and DMH, and predominantlyin the choroid plexus) and is expressed in low density or is absent inperipheral tissues, a selective 5-HT_(2C) receptor agonist can be a moreeffective and safe anti-obesity agent. Also, 5-HT_(2C) knockout mice areoverweight with cognitive impairment and susceptibility to seizure.Thus, the 5HT_(2C) receptor is recognized as a well-accepted receptortarget for the treatment of obesity, psychiatric, and other disorders.

3-Benzazepines have been found to be agonists of the 5HT_(2C) receptorand show effectiveness at reducing obesity in animal models (see, e.g.,U.S. Ser. No. 60/479,280 and U.S. Ser. No. 10/410,991, each of which isincorporated herein by reference in its entirety). Numerous syntheticroutes to 3-benzazepines have been reported and typically involve aphenyl-containing starting material upon which is built an amine- oramide-containing chain that is capable of cyclizing to form the fused7-member ring of the benzazepine core. Syntheses of 3-benzazepines andintermediates thereof are reported in U.S. Ser. No. 60/479,280 and U.S.Ser. No. 10/410,991 as well as Nair et al., Indian J. Chem., 1967, 5,169; Orito et al., Tetrahedron, 1980, 36, 1017; Wu et al., OrganicProcess Research and Development, 1997, 1, 359; Draper et al., OrganicProcess Research and Development, 1998, 2, 175; Draper et al., OrganicProcess Research and Development, 1998, 2, 186; Kuenburg et al., OrganicProcess Research and Development, 1999, 3, 425; Baindur et al., J. Med.Chem.,1992, 35(1), 67; Neumeyer et al., J. Med. Chem., 1990, 33, 521;Clark et al., J. Med. Chem., 1990, 33, 633; Pfeiffer et al., J. Med.Chem., 1982, 25, 352; Weinstock et al., J. Med. Chem., 1980, 23(9), 973;Weinstock et al., J. Med. Chem., 1980, 23(9), 975; Chumpradit et al., J.Med. Chem., 1989, 32, 1431; Heys et al., J. Org. Chem., 1989, 54, 4702;Bremner et al., Progress in Heterocyclic Chemistry, 2001, 13, 340; Hasanet al., Indian J. Chem., 1971, 9(9), 1022; Nagle et al., TetrahedronLetters, 2000, 41, 3011; Robert, et al., J. Org. Chem., 1987, 52, 5594);and Deady et al., J. Chem. Soc., Perkin Trans. I, 1973, 782.

Other routes to 3-benzazepines and related compounds are reported inLadd et al., J. Med. Chem., 1986, 29, 1904; EP 204349; EP 285 919; CH500194; Tetrahedron Letters, 1986, 27, 2023; Ger. Offen., 3418270, 21Nov. 1985; J. Org. Chem., 1985, 50, 743; U.S. Pat. Nos. 4,957,914 and5,015,639; Synthetic Commun., 1988, 18, 671; Tetrahedron, 1985, 41,2557; Hokkaido Daigaku Kogakubu Kenhyu Hokoku, 1979, 96, 414; Chemical &Pharmaceutical Bulletin, 1975, 23, 2584; J. Am. Chem. Soc., 1970, 92,5686; J. Am. Chem. Soc., 1968, 90, 6522; J Am. Chem. Soc., 1968, 90,776; J. Am. Chem. Soc., 1967, 89, 1039; and Chang et al., Bioorg. Med.Chem. Letters, 1992, 2, 399

In view of the growing demand for compounds for the treatment ofdisorders related to the 5-HT_(2C) receptor, new and more efficientroutes to 3-benzazepines are needed. The processes and compoundsdescribed herein help meet these and other needs.

SUMMARY OF THE INVENTION

The processes and intermediates of the present invention are useful inthe preparation of therapeutic agents for the treatment or prophylaxisof 5-HT mediated disorders such as obesity and other central nervoussystem diseases.

The present invention provides, inter alia, a process for preparing acompound of Formula I:

or salt form thereof,wherein:

R¹ is H;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, orally, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising reacting a compound of Formula II:

with a reducing agent optionally in the presence of a Lewis acid for atime and under conditions suitable for forming said compound of FormulaI or salt form thereof.

The present invention further provides a process for preparing acompound of Formula II or salt form thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), —C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰OR¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) nd R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising reacting a compound of Formula III:

or salt form thereof,wherein:

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,or C₁-C₄ haloalkoxy;

R′ is C₁-C₈ alkyl;

with a cyclizing reagent for a time and under conditions suitable forforming said compound of Formula II or salt form thereof.

The present invention further provides a process for preparing acompound of Formula I or salt form thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O-(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkenyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising:

(a) reacting a compound of Formula III:

or salt form thereof,wherein:

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,or C₁-C₄ haloalkoxy; and

R′ is C₁-C₈ alkyl;

with a cyclizing reagent for a time and under conditions suitable forforming a compound of Formula II or salt form thereof; and

(b) reacting said compound of Formula II or salt form thereof with areducing agent optionally in the presence of a Lewis acid for a time andunder conditions suitable for forming said compound of Formula I or saltform thereof.

The present invention further provides a process for preparing acompound of Formula I or salt form thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising:

(a) reacting a compound of Formula IV:

or salt form thereof, with a compound of Formula:

wherein:

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,or C₁-C₄ haloalkoxy;

R′ is C₁-C₈ alkyl; and

Q is a leaving group,

for a time and under conditions suitable for forming a compound ofFormula IIIor salt form thereof;

(b) reacting said compound of Formula III or salt form thereof, with acyclizing reagent for a time and under conditions suitable for forming acompound of Formula II or salt form thereof; and

(c) reacting said compound of Formula II with a reducing agentoptionally in the presence of a Lewis acid for a time and underconditions suitable for forming said compound of Formula I or salt formthereof.

The present invention further provides a process for preparing acompound of Formula I or salt form thereof,

wherein:

R′ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R and R¹¹ together with the Natom to which they are attached form a heterocyclic ring;

comprising reacting a compound of Formula IIIa:

wherein:

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,or C,-C₄ haloalkoxy; and

R′ is C₁-C₈ alkyl;

with a cyclizing reagent for a time and under conditions suitable forforming said compound of Formula I.

The present invention further provides a process for preparing acompound of Formula IIIa or salt form thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7b) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,or C₁-C₄ haloalkoxy; and

R′ is C₁-C₈ alkyl;

comprising reacting a compound of Formula III:

with a reducing agent optionally in the presence of a Lewis acid for atime and under conditions suitable for forming said compound of FormulaIIIa.

The present invention further provides a process for preparing acompound of Formula I or salt form thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising

a) reacting a compound of Formula III

wherein:

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,or C₁-C₄ haloalkoxy; and

R′ is C₁-C₈ alkyl;

with a reducing agent optionally in the presence of a Lewis acid for atime and under conditions suitable for forming a compound of FormulaIIIa;and

b) reacting said compound of Formula IIIa with a cyclizing reagent for atime and under conditions suitable for forming said compound of FormulaI.

The present invention further provides a process for preparing acompound of Formula I or salt form thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising:

(a) reacting a compound of Formula IV

or salt form thereof, with a compound of Formula:

wherein:

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,or C₁-C₄ haloalkoxy;

R′ is C₁-C₈ alkyl; and

Q is a leaving group,

for a time and under conditions suitable for forming a compound ofFormula III or salt form thereof;

(b) reacting said compound of Formula III with a reducing agentoptionally in the presence of a Lewis acid for a time and underconditions suitable for forming a compound of Formula IIIa; and

(c) reacting said compound of Formula IIIa with a cyclizing reagent fora time and under conditions suitable for forming said compound ofFormula I.

The present invention further provides a method of resolving a mixtureof compounds of Formulas Ia and Ib:

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising:

contacting said mixture of compounds with a chiral resolving acid toform chiral resolving acid salts of said compounds, wherein said chiralresolving acid comprises substantially one stereoisomer; and

precipitating said chiral resolving acid salts of said compounds,wherein the resulting precipitate is enriched in the chiral resolvingacid salt of one of said compounds of Formula Ia or Ib.

The present invention further provides a compound of Formula II or IIIaor salt form thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,or C₁-C₄ haloalkoxy; and

R′ is C₁-C₈ alkyl.

The present invention further provides a chiral resolving acid salt of acompound of Formula Ia or Ib

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring.

The present invention further provides a process for preparing acompound of Formula V:

or salt thereof,wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), or C₁-C₄ haloalkyl;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy, OR⁹,alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising reacting a compound of Formula IX:

or salt thereof, wherein x² is halo or SO₂R″ and R″ is C₁-C₈ alkyl,aryl, or heteroaryl each optionally substituted by one or more halo,cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄haloalkoxy, with a cyclizing reagent for a time and under conditionssuitable for forming said compound of Formula V.

The present invention further provides a process for preparing acompound of Formula X:

or salt thereof,wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), or C₁-C₄ haloalkyl;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy, OR⁹,alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-aLkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising reacting a compound of Formula XI:

wherein X¹ is a leaving group,with a compound of Formula:

for a time and under conditions suitable for forming said compound ofFormula X.

The present invention further provides a process for preparing acompound of Formula V or salt thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), or C₁-C₄ haloalkyl;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy, OR⁹,alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising:

a) reacting a compound of Formula X or salt thereof;

with a halogenating/sulfonating reagent for a time and under conditionssuitable for forming a compound of Formula IX or salt thereof;wherein X² is halo or SO₂R″ and R″ is C₁-C₈ alkyl, aryl, or heteroaryleach optionally substituted by one or more halo, cyano, nitro, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkoxy; and

b) reacting said compound of Formula IX with a cyclizing reagent for atime and under conditions suitable for forming said compound of FormulaV.

The present invention further provides a process for preparing acompound of Formula V or salt thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), or C₁-C₄ haloalkyl;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈allcenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising:

a) reacting a compound of Formula XI:

wherein X¹ is a leaving group,with a compound of Formula:

or salt thereof, for a time and under conditions suitable for forming acompound of Formula X or salt thereof;

b) reacting said compound of Formula X with a halogenating/sulfonatingreagent for a time and under conditions suitable for forming a compoundof Formula IX or salt thereof;

wherein X² is halo or SO₂R″ and R″ is C₁-C₈ alkyl, aryl, or heteroaryleach optionally substituted by one or more halo, cyano, nitro, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkoxy; and

c) reacting said compound of Formula IX with a cyclizing reagent for atime and under conditions suitable for forming said compound of FormulaV.

The present invention further provides a process for preparing acompound of Formula V or salt thereof,

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), or C₁-C₄ haloalkyl;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy, OR⁹,alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising:

a) reacting a compound of Formula XII:

with a halogenating/sulfonating reagent for a time and under conditionssuitable for forming a compound of Formula XI wherein X¹ is a leavinggroup;

b) reacting said compound of Formula XI with a compound of Formula:

or salt thereof, for a time and under conditions suitable for forming acompound of Formula X or salt thereof;

c) reacting said compound of Formula X with a furtherhalogenating/sulfonating reagent for a time and under conditionssuitable for forming a compound of Formula IX or salt thereof;

wherein X² is halo or SO₂R″ and R″ is C₁-C₈ alkyl, aryl, or heteroaryleach optionally substituted by one or more halo, cyano, nitro, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkoxy; and

d) reacting said compound of Formula IX with a cyclizing reagent for atime and under conditions suitable for forming said compound of FormulaV.

The present invention further provides a compound of Formula IX or X

or salt form thereof,wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), or C₁-C₄ haloalkyl;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy, OR⁹,alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring; and

X² is halo or SO₂R″; and

R″ is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted byone or more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or C₁-C₄ haloalkoxy.

The present invention further provides a method of resolving a mixtureof compounds of Formula Va and Vb:

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy, OR⁹,alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-CS haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

comprising:

contacting said mixture of compounds with a chiral resolving acid toform chiral resolving acid salts of said compounds, wherein said chiralresolving acid comprises substantially one stereoisomer; and

precipitating said chiral resolving acid salts of said compounds,wherein the resulting precipitate is enriched in the chiral resolvingacid salt of one of said compounds of Formula Va or Vb.

The present invention further provides a chiral resolving acid salt of acompound of Formula Va or Vb

wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy, OR⁹,alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The processes and intermediates of the present invention are useful inthe preparation of therapeutic agents for the treatment or prophylaxisof 5-HT mediated disorders such as obesity and other central nervoussystem diseases.

Example processes and intermediates of the present invention areprovided below in Scheme I, wherein constituent members for thecompounds depicted therein are defined hereinbelow. The symbol “*”designates optionally chiral centers that can be substantially retainedor inverted over the course of the depicted reactions.

In a first aspect of the invention are provided processes, such as areexemplified by Scheme I, that involve compounds of Formulas I, Ia, Ib,II, III, IIIa, and IV,, or salt forms thereof, wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy,mercapto, OR⁹, SR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) and R^(7b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(7a) and R^(7b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

L is halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ thioalkoxy, C₁-C₈ acyloxy,—OSO₂R, or —OSi(R′)₃;

R is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by oneor more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C,-C₄ alkoxy,or C₁-C₄ haloalkoxy; and

R′ is C₁-C₈ alkyl.

In some embodiments:

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, or CH₂OH;

R³ and R⁶ are each H;

R⁴ and R⁵ are each, independently, H, halo, C₁-C₈ haloalkyl, hydroxy,OR⁹, SR⁹, alkoxyalkyl, NHR¹⁰, NR¹⁰OR¹¹, aryl, or heteroaryl, whereinsaid aryl can be substituted with up to two substituents selected fromC₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy, and said heteroaryl canbe optionally substituted with up to two substituents selected fromhalogen and C₁-C₈ alkyl; or R⁴ and R⁵ together with the atoms to whichthey are attached form a 5- or 6-member heterocyclic ring having one Oatom;

R^(7a) is H;

R^(7b) is H or C₁-C₈ alkyl;

R_(8a) and R^(8b) are each H; and

R¹⁰ and R¹¹ are each, independently, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈haloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or allyl.

In some embodiments, (A) if R² is methyl and R⁴ is H, then R⁵ is notthiazole, substituted thiazole or a thiazole derivative;

In some embodiments, (B) if R^(7a) is H and R^(7b) is other than H, thenneither R⁴ nor R⁵ can be H;

In some embodiments, (C) if R¹ and R² are methyl, and R⁵ is H then R⁴ isnot NHR¹⁰ or NR¹⁰R¹¹;

In some embodiments, (D) if R¹ and R² are methyl and R⁵ is H, then R⁴ isnot imidazolyl, substituted imidazolyl, or an imidazole derivative;

In some embodiments, (E) if R¹ is H or CH₃, and R² is CH₃ or OH, thenR³, R⁴, R⁵, and R⁶ cannot all be H.

In some embodiments, (F) if R¹ is H and R² is isopropyl or OH, then R⁴and R⁵ cannot both be OCH₃ or OH.

In some embodiments, (G) if R¹ is CH₃ and R² is n-propyl, then R⁴ cannotbe OH, R⁵ cannot Cl, and R³ and R⁶ cannot both be H.

In further embodiments, R¹ is H.

In further embodiments, R¹ is C₁-C₈ alkyl.

In further embodiments, R² is methyl, ethyl, n-propyl, or isopropyl.

In further embodiments, R² is methyl.

In further embodiments, R⁴ is Cl, Br, haloalkyl, CF₃, thiophenyl,furanyl, pyrrolyl, pyrazolyl, or imidazolyl.

In further embodiments, R⁴ is Cl.

In further embodiments, R⁵ is methoxy, ethoxy, n-propoxy, isopropoxy,allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, orphenyl, wherein said imidazolyl is optionally substituted by one or morehalo or methyl and said phenyl is optionally substituted with up to twosubstituents selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl, halo, andalkoxy.

In further embodiments, R⁵ is H.

In some embodiments:

R² is C₁-C₄ alkyl, —CH₂—O—(C₁-C₄ alkyl), C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, hydroxy, NH₂, CN, or NO₂; and

R^(7a), R^(7b), R^(8a), and R^(8b) are each H.

In some embodiments, (H) when R² is C₁-C₄ alkyl, —CH₂—O—(C₁-C₄ alkyl),or CH₂OH, then R³ and R⁶ are not both H; and

In some embodiments, (I) when R² is CH₃, then R³, R⁴, and R⁶ are each Hand R⁵ is not H or isopropyl.

In further embodiments, R¹ is H.

In further embodiments, R¹ is C₁-C₈ alkyl.

In further embodiments, R² is C₁-C₄ alkyl or C₁-C₄ haloalkyl.

In further embodiments, R² is methyl, ethyl, isopropyl, n-butyl, or CF₃.

In further embodiments, R³, R⁴, R⁵, and R⁶ are each, independently, H,methyl, NH₂, CN, halo, CF₃, NO₂, or OH.

In further embodiments of the invention, R^(7a), R^(7b), R^(8a), andR^(8b) are each H.

In further embodiments of the invention, R³ and R⁶ are each H.

In further embodiments of the invention, R³, R⁵, and R⁶ are each H.

In further embodiments of the invention, R⁴ is halo.

In further embodiments of the invention, R⁴ is Cl.

In further embodiments of the invention, R² is C₁-C₄ alkyl.

In further embodiments of the invention, R² is methyl.

In further embodiments of the invention, R¹ is H.

In further embodiments of the invention, R¹ is H or C₁-C₄ alkyl, R² isC₁-C₄ alkyl, R³ is H, R⁴ is halo, R⁵ is H, R⁶ is H, R^(7a) is H, R^(7b)is H, R^(8a) is H, and R^(8b) is H.

In further embodiments of the invention, R¹ is H, R² is Me, R³ is H, R⁴is Cl, R⁵ is H, R⁶ is H, R^(7a) is H, R^(7b) is H, R^(8a) is H, andR^(8b) is H.

In further embodiments of the invention, L is halo.

In further embodiments of the invention, L is hydroxy.

In further embodiments of the invention, L is Cl.

In further embodiments of the invention, L is Br.

In further embodiments of the invention, L is —OSO₂R such as sulfonates(e.g., mesylate, triflate, methyl sulfonate).

In further embodiments of the invention, L is —OSi(R′)₃ such astrimethylsilyloxy.

In further embodiments of the invention, the compound of Formula I hasan S configuration at the carbon bearing R².

In further embodiments of the invention, the compound of Formula I hasan R configuration at the carbon bearing R².

The present invention provides a process for preparing a compound ofFormula I:

or salt form thereof,comprising reacting a compound of Formula II:

with a reducing agent optionally in the presence of a Lewis acid for atime and under conditions suitable for forming the compound of Formula Ior salt form thereof.

In some embodiments, the reducing agent comprises a borane such as BH₃.In further embodiments, the reducing agent comprises a metal hydridesuch as a borohydride or aluminum hydride. In some embodiments, thereducing agent is BH₃:TBF. Other reducing agents are suitable and can beselected by one skilled in the art. Example suitable reducing agents arecompounds that selectively reduce the amide moiety of the compound ofFormula II.

In further embodiments, a Lewis acid can be present in the reaction inan amount sufficient to increase reaction rate. Suitable Lewis acidsinclude boron-containing Lewis acids such as BF₃ and adducts thereofincluding BF₃:TBME (t-butyl methyl ether); BF₃:OEt₂;BF₃:O(CH₂CH₂CH₂CH₃)₂; BF₃:THF; and the like. Suitable amounts includefrom about 0.01 eq to about 1 eq relative to amount of compound ofFormula II.

Due to potential sensitivity of the reducing agent to air, the reactioncan be conducted under an inert atmosphere.

Reacting can be carried out in any inert solvent such as a dialkyletheror cyclic ether (e.g., THF) at any suitable temperature, such as roomtemperature. The duration of the reduction can be carried out for anyamount of time determined by one skilled in the art. In someembodiments, the reaction duration is sufficient to allow the reactionto go substantially to completion. For example, reaction durations canrange from about 10 minutes to about 48 hours. In some embodiments, thereaction duration is about 8-12 hours. Reaction completion can bemonitored, for example, by LC/MS.

The amount of reducing agent provided is typically sufficient to provideat least enough reducing equivalents to reduce the compound of FormulaII to the desired product. For example, an excess of reducing agent canbe provided such as about 10×, about 5×, about 3×, or about 2× reducingequivalent excess. For boranes and related reducing agents, the molarratio of reducing agent to the compound of Formula II can be, forexample, about 2:1, about 3:1, about 5:1, or about 10:1. In someembodiments, the molar ratio is about 3:1.

In some embodiments, the yield for the reduction reaction (based onamount of compound of Formula II), is greater than about 50%, about 60%,about 70%, about 80%, or about 90%.

The present invention further provides a process for preparing acompound of Formula II, or salt form thereof, comprising reacting acompound of Formula III:

or salt form thereof, with a cyclizing reagent for a time and underconditions suitable for forming the compound of Formula II or salt formthereof.

In some embodiments, L of the compound of Formula III is halo. Infurther embodiments, L of the compound of Formula III is Cl.

In some embodiments, the cyclizing reagent includes a Lewis acid, suchas, for example, a C₁-C₈ alkyl aluminum halide (e.g., methyl aluminumchloride, ethyl aluminum chloride, etc.), a C₂-C₁₆ dialkyl aluminumhalide (e.g., dimethyl aluminum chloride, diethyl aluminum chloride,etc.), trialkylaluminum, AlCl₃, or AlBr₃. In some embodiments, thecyclizing reagent is AlCl₃. Other suitable cyclizing reagents includeacids such as sulfuric acid.

Cyclization can be carried out in the absence of solvent or in thepresence of solvent. Suitable solvents include non-polar or weakly polarsolvents such as decahydronaphthalene or 1,2-dichlorobenzene. Othersuitable solvents include haloalkanes and other halogenated aromaticssuch as 1,3-dichlorobenzene and 1,4-dichlorobenzene.

The cyclizing reagent can be provided in an amount suitable formaximizing the yield of the cyclized product. In some embodiments, thecyclizing reagent can be provided in molar excess relative to the amountof compound of Formula III. Example molar ratios of cyclizing reagent tocompound of Formula III include about 2:1, about 3: 1, about 5: 1, orabout 10:1. In some embodiments, the molar ratio is about 3:1.

In further embodiments, cyclization is carried out at elevatedtemperature such as at about 80 to about 160° C. In some embodiments,cyclization is carried out at about 150° C. The cyclization reaction canbe monitored by LC/MS. Duration to substantial completion can be about10 minutes to about 24 hours. In some embodiments, reaction duration isfrom about 3 hours to about 15 hours.

In some embodiments, the yield for the cyclization reaction (based onamount of compound of Formula III), is greater than about 40%, about50%, about 60%, about 70%, about 80%, or about 90%.

The present invention further provides preparing a compound of FormulaIII comprising reacting a compound of Formula IV:

or salt form thereof, with a compound of Formula:

wherein Q is a leaving group, for a time and under conditions suitablefor forming the compound of Formula III or salt form thereof.

According to some embodiments, Q is hydroxy, alkoxy, halo, orO(CO)R^(Q), wherein R^(Q) is C₁-C₈ alkyl, C₃-C₇ cycloalkyl, aryl,heteroaryl, or heterocycloalkyl. In some embodiments, Q is halo such asCl. In other embodiments, Q is hydroxy. In yet other embodiments, Q isalkoxy, such as methoxy, anthony, or t-butoxy.

Amide formation can be optionally carried out in the presence of basesuch as an amine (e.g., NMe₃, Nat₃, morpholine, pyridine,diisopropylethylamine, piperidine, N,N-dimethylaminopiperidine, and thelike). Other suitable bases include inorganic bases such as NaOH, KOP,CsOH, and the like.

Relative amounts of reagents suitable for carrying out the reactioninclude about molar equivalents of each. For example, the amideformation reaction can be carried out with a molar ratio of compound ofFormula IV to compound of Formula:

of about 1:1. In further embodiments, an equivalent amount of base canalso be included (e.g., molar ratio of about 1:1:1). In yet furtherembodiments, base can be added in excess relative to the amount ofcompound of Formula IV.

In further embodiments, the amide formation reaction can be carried outin solvent, such a polar solvent. An example of a polar solvent isacetonitrile. Reaction temperature can vary from about −10 to about 30°C. In some embodiments, the reaction can start at a temperature belowroom temperature such as about 0° C., and for the reaction duration,rise to about room temperature. Reaction progress can be monitored, forexample, by TLC, and time to completion can be from about 10 minutes toabout 5 hours, depending on, for example, scale of the reaction.

In some embodiments, the yield for the amide formation reaction (basedon amount of compound of Formula IV), is greater than about 40%, about50%, about 60%, about 70%, about 80%, or about 90%.

In an alternate route to compounds of Formula I, the present inventionprovides a process for preparing a compound of Formula I:

or salt form thereof, comprising reacting a compound of Formula IIIa:

with a cyclizing reagent for a time and under conditions suitable forforming the compound of Formula I.

In some embodiments, L of the compound of Formula IIIa is halo. Infurther embodiments, L of the compound of Formula IIIa is Br or Cl.

In some embodiments, the cyclizing reagent includes a Lewis acid, suchas, for example, a C₁-C₈ alkyl aluminum halide (e.g., methyl aluminumchloride, ethyl aluminum chloride, etc.), a C₂-C₁₆ dialkyl aluminumhalide (e.g., dimethyl aluminum chloride, diethyl aluminum chloride,etc.), trialkylaluminum, AlCl₃, or AlBr₃. Other suitable cyclizingreagents include acids such as sulfuric acid.

Cyclization can be carried out in the absence of solvent or in thepresence of solvent. Suitable solvents include non-polar or weakly polarsolvents such as decahydronaphthalene or 1,2-dichlorobenzene. Othersuitable solvents include haloalkanes and other halogenated aromaticssuch as 1,3-dichlorobenzene and 1,4-dichlorobenzene.

The cyclizing reagent can be provided in an amount suitable formaximizing the yield of the cyclized product. In some embodiments, thecyclizing reagent can be provided in molar excess relative to the amountof compound of Formula IIIa. Example molar ratios of cyclizing reagentto compound of Formula IIIa include about 2:1, about 3:1, about 5:1, orabout 10:1. In some embodiments, the molar ratio is about 3:1.

In further embodiments, cyclization is carried out at elevatedtemperature such as at about 80 to about 160° C. In some embodiments,cyclization is carried out at about 140° C. The cyclization reaction canbe monitored by LC/MS. Duration to completion can be about 10 minutes toabout 24 hours. In some embodiments, reaction duration is from about 3hours to about 15 hours.

In some embodiments, the yield for the cyclization reaction (based onamount of compound of Formula IIIa), is greater than about 40%, about50%, about 60%, about 70%, about 80%, or about 90%.

The present invention further provides a process for preparing acompound of Formula IIIa, or salt form thereof, comprising reacting acompound of Formula III:

with a reducing agent optionally in the presence of a Lewis acid for atime and under conditions suitable for forming said compound of FormulaIIIa.

In some embodiments, the reduction of III can be carried out so that thestereochemistry of one or more chiral centers present in the compound ofFormula III is substantially retained in the reduced product (FormulaIIIa). In further embodiments, the reduction of ma can be carried outusing a substantially pure stereoisomer of ma. In yet furtherembodiments, the reduction of IIIa can be carried out using asubstantially pure stereoisomer of ma and result in a substantially purestereoisomer of III. For example, a compound of Formula III having ee ofgreater than about 80, about 90, or about 95% can reduced to form acompound of Formula IIIa having a similar ee.

In some embodiments, the reducing agent comprises a borane such as BH₃.In further embodiments, the reducing agent comprises a metal hydridesuch as a borohydride or aluminum hydride. In some embodiments, thereducing agent is BH₃:THF. Other reducing agents are suitable and can beselected by one skilled in the art. Example suitable reducing agents arecompounds that selectively reduce the amide moiety of the compound ofFormula II.

In further embodiments, a Lewis acid can be present in the reaction inan amount sufficient to increase reaction rate. Suitable Lewis acidsinclude boron-containing Lewis acids such as BF₃ and adducts thereofincluding BF₃:TBME (t-butyl methyl ether); BF₃:OEt₂;BF₃:O(CH₂CH₂CH₂CH₃)₂; BF₃:THF; and the like. Suitable amounts includefrom about 0.01 eq to about 1 eq relative to amount of compound ofFormula III.

Due to potential sensitivity of the reducing agent to air, the reactioncan be conducted under an inert atmosphere.

The reduction reaction can be carried out in inert solvent such as adialkylether or cyclic ether (e.g., TBF) at any suitable temperature,such as room temperature. The duration of the reduction can be carriedout for any amount of time. In some embodiments, the reaction durationis sufficient to allow the reaction to go substantially to completion.For example, reaction durations can range from about 10 minutes to about72 hours. In some embodiments, the reaction duration is about 8-12hours. Reaction completion can be monitored, for example, by LC/MS.

The amount of reducing agent provided is typically sufficient to provideat least enough reducing equivalents to reduce the compound of FormulaII to the desired product. For example, an excess of reducing agent canbe provided such as about 10×, 5×, 3×, or 2× reducing equivalent excess.For boranes and related reducing agents, the molar ratio of reducingagent to the compound of Formula II can be, for example, 2:1, 3:1, 5:1,or 10:1. In some embodiments, the molar ratio is 3:1.

In some embodiments, the yield for the reduction reaction (based onamount of compound of Formula III), is greater than about 50%, about60%, about 70%, about 80%, or about 90%.

The present invention further provides processes provided below inSchemes Ia, Ib and Ic, wherein constituent members of the structuresdepicted therein are defined above.

In further embodiments, the present invention provides a method ofresolving a mixture of compounds of Formulas Ia and Ib:

by contacting the mixture of compounds with a chiral resolving acidenriched in one stereoisomer (e.g., ee greater than about 50%, about75%, about 90% or about 95%) to form chiral resolving acid salts of thecompounds of the mixture, and then precipitating the chiral resolvingacid salts. The resulting precipitate is typically enriched in thechiral resolving acid salt of one of the compounds of Formulas Ia or Ib(e.g., ee>50%). In some embodiments, the precipitate is enriched in thechiral resolving acid salt form of the compound of Formula Ia. In someembodiments, the precipitate is enriched in the chiral resolving acidsalt form of the compound of Formula Ib. In further embodiments, thechiral resolving acid is a stereoisomer of toluoyl tartaric acid,camphoric acid, ketogulonic acid, or tartaric acid. In furtherembodiments, the chiral resolving acid is a stereoisomer of tartaricacid such as L-(+)-tartaric acid.

Contacting of compounds with a chiral resolving acid can be carried outin solution. Suitable solvents support dissolution of both the chiralresolving acid and the compounds of Formulas Ia and Ib. Some examplesolvents include polar solvents or water-miscible solvents such asalcohols (e.g., methanol, ethanol, isopropanol, t-butanol, and thelike), isopropylacetate, water, and mixtures thereof. In furtherembodiments, the solvent contains a mixture of t-butanol and water. Someexample mixtures include about 5-25% water and about 75-95% t-butanol.In some embodiments, the solvent contains about 8-12% water and about88-92% of t-butanol.

Precipitate containing the chiral resolving acid salt forms can beformed by precipitation from any suitable solvent which dissolves thesalts such as the solvent in which contacting was carried out.Precipitation can be induced by any method known in the art such as byheating a solution containing the mixture of salts followed by cooling.Precipitate can be separated from the solvent by, for example,filtration. Enrichment of the precipitate in one chiral salt over theother can be characterized by an enantiomeric excess (ee) of greaterthan about 50%, about 60%, about 70%, about 80%, about 90%, about 95%,about 98%, or about 99%. In some embodiments, ee is greater than about80%. Precipitation can be repeated one or more times to increase theproportion of a chiral salt in the precipitate by re-dissolving andre-precipitating previously obtained precipitate.

The present invention further provides a chiral resolving acid salt of acompound of Formula Ia or Ib:

wherein constituent members are defined hereinabove. Compositions of thepresent invention can contain one or or both the salt form of a compoundof Formula Ia and the salt form of a compound of Formula Ib. In someembodiments, the salt form of the compound of Formula Ia is present inthe composition in an amount greater than the salt form of a compound ofFormula Ib. In other embodiments, the salt form of the compound ofFormula Ib is present in the composition in an amount greater than thesalt form of a compound of Formula Ia.

Further example processes and intermediates of the present invention areprovided below in Scheme II, where constituent members of compoundsdepicted therein are defined hereinbelow. The symbol “*” designatesoptionally chiral centers that can be substantially retained or invertedover the course of the depicted reactions.

In a second aspect of the present invention are provided processes, suchas are exemplified by Scheme II, that involve compounds of Formulas V,Va, Vb, IX, X, XI, and XII, or salt forms thereof, wherein:

R¹ is H or C₁-C₈ alkyl;

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),—C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, hydroxy, OR⁹,alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl,NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl, wherein saidaryl and heteroaryl can be substituted with one or more substituentsselected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, and alkoxy; or R⁴ andR⁵ together with the atoms to which they are attached form a 5- or6-member heterocyclic ring having one O atom;

R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group;

R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl,C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl;and

R¹⁰ and R¹¹ are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl,heteroaryl, heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with theN atom to which they are attached form a heterocyclic ring;

X¹ is a leaving group;

X² is halo or SO₂R″; and

R″ is C₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted byone or more halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or C₁-C₄ haloalkoxy.

In some embodiments of the invention:

R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl),-C(O)NH-(C₁-C₈ alkyl), OH, or CH₂OH;

R³ and R⁶ are each H;

R⁴ and R⁵ are each, independently, H, halo, C₁-C₈ haloalkyl, hydroxy,OR⁹, SR⁹, alkoxyalkyl, NHR¹⁰, NR¹⁰R¹¹, aryl, or heteroaryl, wherein saidaryl can be substituted with up to two substituents selected from C₁-C₈alkyl, halo, C₁-C₈ haloalkyl, and alkoxy, and said heteroaryl can beoptionally substituted with up to two substituents selected from halogenand C₁-C₈ alkyl; or R⁴ and R⁵ together with the atoms to which they areattached form a 5- or 6-member heterocyclic ring having one O atom;

R^(7a) is H;

R^(7b) is H or C₁-C₈ alkyl;

R^(8a) and R^(8b) are each H; and

R¹⁰ and R¹¹ are each, independently, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈haloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or allyl.

In some embodiments, (A) if R² is methyl and R⁴ is H, then R⁵ is notthiazole, substituted thiazole or a thiazole derivative.

In some embodiments, (B) if R^(7a) is H and R^(7b) is other than H, thenneither R⁴ nor R⁵ can be H.

In some embodiments, (C) if R¹ and R² are methyl, and R⁵is H then R⁴ isnot NHR¹⁰ or NR¹⁰R¹¹.

In some embodiments, (D) if R¹ and R² are methyl and R⁵ is H, then R⁴ isnot imidazolyl, substituted imidazolyl, or an imidazole derivative.

In some embodiments, (E) if R¹ is H or CH₃, and R² is CH₃ or OH, thenR³, R⁴, R⁵, and R⁶ cannot all be H.

In some embodiments, (F) if R¹ is H and R² is isopropyl or OH, then R⁴and R⁵ cannot both be OCH₃ or OH.

In some embodiments, (G) if R¹ is CH₃ and R² is n-propyl, then R⁴ cannotbe OH, R⁵ cannot Cl, and R³ and R⁶ cannot both be H.

In further embodiments, R¹ is H.

In further embodiments, R¹ is C₁-C₈ alkyl.

In further embodiments, R² is methyl, ethyl, n-propyl, or isopropyl.

In further embodiments, R² is methyl.

In further embodiments, R⁴ is Cl, Br, haloalkyl, CF₃, thiophenyl,furanyl, pyrrolyl, pyrazolyl, or imidazolyl.

In further embodiments, R⁴ is Cl.

In further embodiments, R⁵ is methoxy, ethoxy, n-propoxy, isopropoxy,allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, orphenyl, wherein said imidazolyl is optionally substituted by one or morehalo or methyl and said phenyl is optionally substituted with up to twosubstituents selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl, halo, andalkoxy.

In further embodiments, R⁵ is H.

In some embodiments:

R² is C₁-C₄ alkyl, —CH₂—O—(C₁-C₄ alkyl), C₁-C₄ haloalkyl, or CH₂OH;

R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₄ alkyl, C₁-C₄haloalkyl, hydroxy, NH₂, CN, or NO₂; and

R^(7a), R^(7b), R^(8a), and R^(8b) are each H.

In some embodiments, (H) when R² is C₁-C₄ alkyl, —CH₂—O—(C₁-C₄ alkyl),or CH₂OH, then R³ and R⁶ are not both H.

In some embodiments, (I) when R² is CH₃, then R³, R⁴, and R⁶ are each Hand R⁵ is not H or isopropyl.

In further embodiments, R′ is H.

In further embodiments, R′ is C₁-C₈ alkyl.

In further embodiments, R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈ alkyl),C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), or C₁-C₄ haloalkyl;

In further embodiments, R² is C₁-C₄ alkyl or C₁-C₄ haloalkyl.

In further embodiments, R² is methyl, ethyl, isopropyl, n-butyl, or CF₃.

In further embodiments, R³, R⁴, R⁵, and R⁶ are each, independently, H,methyl, NH₂, CN, halo, CF₃, NO₂, or OH.

In further embodiments of the invention, R^(7a), R^(7b), R^(8a), andR^(8b) are each H.

In further embodiments of the invention, R³ and R⁶ are each H.

In further embodiments of the invention, R³, R⁵, and R⁶ are each H.

In further embodiments of the invention, R⁴ is halo.

In further embodiments of the invention, R⁴ is Cl.

In further embodiments of the invention, R² is C₁-C₄ alkyl.

In further embodiments of the invention, R² is methyl.

In further embodiments of the invention, R¹ is H.

In further embodiments, X¹ is halo.

In further embodiments, X¹ is Br.

In further embodiments, X¹ is Cl.

In further embodiments, X² is halo.

In further embodiments, X² is Br.

In further embodiments, X² is Cl.

In further embodiments of the invention, R¹ is H or C₁-C₄ alkyl, R² isC₁-C₄ alkyl, R³ is H, R⁴ is halo, R⁵ is H, R⁶ is H, R^(7a) is H, R^(7b)is H, R^(8a) is H, and R^(8b) is H.

In further embodiments of the invention, R¹ is H, R² is Me, R³ is H, R⁴is Cl, R⁵ is H, R⁶ is H, R⁷a is H, R^(7b) is H, R^(8a) is H, and R^(8b)is H.

In further embodiments of the invention, the compound of Formula V hasan S configuration at the carbon bearing R².

In further embodiments of the invention, the compound of Formula V hasan R configuration at the carbon bearing R².

The present invention provides a process for preparing a compound ofFormula V:

or salt thereof, by reacting a compound of Formula IX:

or salt thereof, with a cyclizing reagent for a time and underconditions suitable for forming the compound of Formula V.

In some embodiments, the cyclizing reagent includes a Lewis acid, suchas, for example, a C₁-C₈ alkyl aluminum halide (e.g., methyl aluminumchloride, ethyl aluminum chloride, etc.), a C₂-C₁₆ dialkyl aluminumhalide (e.g., dimethyl aluminum chloride, diethyl aluminum chloride,etc.), trialkylaluminum, AlCl₃, or AlBr₃. Other suitable cyclizingreagents include acids such)as sulfuric acid.

The cyclizing reagent can be provided in an amount suitable formaximizing the yield of the cyclized product. In some embodiments, thecyclizing reagent can be provided in molar excess relative to the amountof compound of Formula IX. Example molar ratios of cyclizing reagent tocompound of Formula IX include about 1.5:1, about 2:1, about 3:1, about5:1, or about 10:1. In some embodiments, the molar ratio is about 1.5:1.

Reacting can be carried out in the presence of any suitable solvent (orin the absence of solvent) such as a non-polar or weakly-polar solventor a high boiling solvent (boiling point greater than for water). Insome embodiments, reacting can be carried out in the presence of1,2-dichlorobenzene. In further embodiments, reacting can be carried outin the presence of decalin.

Reaction temperature can be any suitable temperature such astemperatures that do not readily degrade the reactants yet maximizereaction efficiency and/or minimize reaction time. In some embodiments,reacting is carried out at an elevated temperature such as, for example,between about 80 and about 170° C. In some embodiments, elevatedtemperature is from about 100 to about 150, about 120 to about 150, orabout 140° C.

The cyclization reaction can be monitored by LC/MS. Duration tocompletion can be about 10 minutes to about 24 hours. In someembodiments, reaction duration is from about 3 hours to about 15 hours.In further embodiments, reaction duration is about 2 to 5 hours.

In some embodiments, the yield for the cyclization reaction (based onamount of compound of Formula IX), is greater than about 40%, about 50%,about 60%, about 70%, about 80%, or about 90%.

The present invention further provides a process for preparing acompound of Formula IX:

or salt thereof, by reacting a compound of Formula X:

or salt thereof, with a halogenating/sulfonating reagent for a time andunder conditions suitable for forming the compound of Formula XI.

Suitable halogenating/sulfonating reagents are capable of replacing theOH moiety in the compound of Formula X with a halogen atom or sulfonatemoiety. In some embodiments, the halogenating/sulfonating reagent isSOBr₂ or SOCl₂.

The halogenating/sulfonating reagent can be provided in an amountsufficient to theoretically produce maximum yield. Suitable molar ratiosof halogenating/sulfonating reagent to compound of Formula X include theratios of about 10:1, about 5:1, about 3:1, about 2:1, or about 1.5:1.In some embodiments, the molar ratio is about 1.06:1 to about 1.4:1.

Reacting can be carried out in any suitable solvent or in the absence ofsolvent, such as solvents capable of dissolving at least one of thecompound of Formula X or the halogenating/sulfonating reactant. In someembodiments, the solvent contains DMF (dimethylformamide). In furtherembodiments, the solvent contains toluene. In yet further embodiments,the solvent contains dichloromethane. In some embodiments, the solventcontains dimethylformamide and toluene, and in further embodiments, thesolvent contains dimethylformamide and dichloromethane.

Any reaction temperature that does not substantially decompose thestarting materials, solvent, or products is suitable. In someembodiments, reacting is carried out at temperatures such as from about40 to about 80° C., about −10 to about 30° C., or about 0° C. to aboutroom temperature.

In some embodiments, the compound of Formula XI is isolated, such as byrecrystallization from a suitable solvent. Yield can be greater thanabout 20%, greater than about 30%, greater than about 40%, or greaterthan about 50%. In some embodiments, yield is greater than about 50%.

The present invention also provides a process for preparing a compoundof Formula X:

or salt thereof,comprising reacting a compound of Formula XI:

with a compound of Formula:

for a time and under conditions suitable for forming the compound ofFormula X.

The reacting can be carried out, for example, at elevated temperaturesuch as from about 80 to about 110° C. or 90 to about 100° C. In someembodiments, reacting is carried out at about 95° C.

Any suitable inert solvent can be used, and in some embodiments,reacting is carried out in the absence of solvent.

A sufficient amount of compound of Formula:

can be provided in the reaction to obtain a theoretical or empiricalmaximum yield. Example amounts can range from at least about 1 molarequivalent to any amount that would be in molar excess (e.g., about 10×or 15×) relative to the amount of compound of Formula XI.

An example reaction duration can be from about 3 to about 5 hours.

The present invention further provides a process of preparing a compoundof Formula XI by reacting a compound of Formula XII:

with a halogenating/sulfonating reagent for a time and under conditionssuitable for forming the compound of Formula XI.

The halogenating/sulfonating reagent can be any suitable reagent capableof replacing the hydroxy moiety of the compound of Formula XII with asutiable leaving group such as a halogen atom or sulfonate moiety. Insome embodiments, the halogenating/sulfonating reagent is, for example,PBr₃ or PCl₃.

Any suitable solvent can be used or the reacting can be carried out inthe absence of solvent.

Reaction temperature can be readily selected by the art skilled. In someembodiments, reacting is carried out at lowered temperatures such asfrom about −20 to about 15° C., about −10 to about 10° C., or about 0°C. In some embodiments, the reaction temperature is below about 10° C.

Halogenating/sulfonating reagent can be provided in an amount sufficientto produce maximum theoretical yield. For example, the molar ratio ofhalogenating/sulfonating reagent to compound of Formula XII can rangefrom about 20:1 to about 0.2:1. In some embodiments,halogenating/sulfonating reagent is provided in slight excess, such asin a ratio of about 1:1 or about 0.5:1.

Reaction yield can be greater than about 75%, greater than about 85%,greater than about 90%, greater than about 95, or greater than about98%. In some embodiments, yield is from about 95% to about 100%.

In further embodiments, the present invention provides a method ofresolving a mixture of compounds of Formulas Va and Vb:

by contacting the mixture of compounds with a chiral resolving acidenriched in one stereoisomer (e.g., ee greater than about 50%, about75%, about 90% or about 95%) to form chiral resolving acid salts of thecompounds of the mixture, and then precipitating the chiral resolvingacid salts. The resulting precipitate is typically enriched in thechiral resolving acid salt of one of the compounds of Formulas Va or Vb(e.g., ee>50%). In some embodiments, the precipitate is enriched in thechiral resolving acid salt form of the compound of Formula Va. In someembodiments, the precipitate is enriched in the chiral resolving acidsalt form of the compound of Formula Vb. In further embodiments, thechiral resolving acid is a stereoisomer of toluoyl tartaric acid,camphoric acid, ketogulonic acid, or tartaric acid. In furtherembodiments, the chiral resolving acid is tartaric acid such asL-(+)-tartaric acid.

Contacting of compounds of Formulas Va and Vb with a chiral resolvingacid can be carried out in solution. Suitable solvents supportdissolution of both the chiral resolving acid and the compounds ofFormulas Va and Vb. Some example solvents include polar solvents orwater-miscible solvents such as alcohols (e.g., methanol, ethanol,isopropanol, t-butanol, 1-butanol and the like), isopropylacetate,tetrahydrofuran, acetone, methyl isobutyl ketone, water, and mixturesthereof. In some embodiments, the solvent contains a mixture of alcoholand water. In further embodiments, the solvent contains a mixture oft-butanol and water. Some example mixtures include about 5-25% water andabout 75-95% t-butanol. In some embodiments, the solvent contains about8-12% water and about 88-92% of t-butanol. In some embodiments, thesolvent contains a mixture of acetone and water.

Precipitate containing the chiral resolving acid salt forms can beformed by precipitation from any suitable solvent which dissolves thesalts such as the solvent in which contacting was carried out.Precipitation can be induced by any method known in the art such as byheating a solution containing the mixture of salts followed by cooling.Precipitate can be separated from the solvent by, for example,filtration. Enrichment of the precipitate in one chiral salt over theother can be characterized by an enantiomeric excess (ee) of greaterthan about 50%, about 60%, about 70%, about 80%, about 90%, about 95%,about 98%, or about 99%. In some embodiments, ee is greater than about80%. Precipitation can be repeated one or more times to increase theproportion of a chiral salt in the precipitate by re-dissolving andre-precipitating previously obtained precipitate.

The present invention further provides a chiral resolving acid salt of acompound of Formula Va or Vb:

wherein constituent members are defined hereinabove. Compositions of thepresent invention can contain one or or both the salt form of a compoundof Formula Va and the salt form of a compound of Formula Vb. In someembodiments, the salt form of the compound of Formula Va is present inthe composition in an amount greater than the salt form of a compound ofFormula Vb. In other embodiments, the salt form of the compound ofFormula Vb is present in the composition in an amount greater than thesalt form of a compound of Formula Va.

The present invention further provides a hydrochloric acid salt of acompound of Formula Va or Vb and compositions thereof.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like. An alkyl group in which all of thehydrogen atoms are replaced with halogen atoms can be referred to as“perhaloalkyl.”

As used herein, “aryl” refers to monocyclic or polycyclic aromatichydrocarbons such as, for example, phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 6 to about 20 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic hydrocarbonsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono-, bi- or poly-cyclic ring systems as well as double andtriple bonds. Example cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,adamantyl, and the like. Also included in the definition of cycloalkylare moieties that have one or more aromatic rings fused (i.e., having abond in common with) to the cycloalkyl ring, for example, benzoderivatives of pentane, hexane, and the like.

As used herein, “heteroaryl” groups are monocyclic and polycyclicaromatic hydrocarbons that have at least one heteroatom ring member suchas sulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and thelike. In some embodiments, heteroaryl groups can have from 1 to about 20carbon atoms, and in further embodiments from about 3 to about 20 carbonatoms. In some embodiments, heteroaryl groups have 1 to about 4, 1 toabout 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to a cycloalkyl group whereinone or more of the ring-forming carbon atoms is replaced by a heteroatomsuch as an O, S, N, or P atom. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the nonaromatic heterocyclicring, for example phthalimidyl, naphthalimidyl pyromellitic diimidyl,phthalanyl, and benzo derivatives of saturated heterocycles such asindolene and isoindolene groups.

As used herein, “halo” or “halogen” includes floury, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “thioalkoxy” refers to an alkoxy group in which the Oatom is replaced by an S atom.

As used herein, “aryloxy” refers to an —O-aryl group. An example aryloxygroup is phenoxy.

As used herein, “thioaryloxy” refers to an aryloxy group in which the Oatom is replaced by an S atom.

As used herein, “aralkyl” refers to an alkyl moiety substituted by anaryl group. Example aralkyl groups include benzyl, phenethyl, andnaphthylmethyl groups. In some embodiments, arylalkyl groups have from 7to 20 or 7 to 11 carbon atoms.

As used herein, “hydroxyalkyl” refers to an alkyl group substituted byhydroxy.

As used herein, “alkoxyalkyl” refers to an alkyl group substituted by analkoxy group.

As used herein, the term “reacting” is used as known in the art andgenerally refers to the bringing together of chemical reagents in such amanner so as to allow their interaction at the molecular level toachieve a chemical or physical transformation.

As used herein, the term “substituted” refers to the replacement of ahydrogen moiety with a non-hydrogen moiety in a molecule or group.

As used herein, the term “thiazole derivative” refers to a moietycontaining a thiazolyl group.

As used herein, the term “imidazole derivative” refers to a moietycontaining a imidazolyl group.

As used herein, the term “contacting” refers to the bringing together ofsubstances so that they can interact at the molecular level.

As used herein, the term “reducing agent” is used as known in the artand refers to any chemical reagent that carries out the reduction ofanother chemical reagent. In some embodiments, a reduction carried outby a reducing agent involves lowering the number of bonds of an atom(e.g., a C atom) to oxygen or sulfur. For example, a reducing agent canconvert (or reduce) a ketone to an alcohol. In some embodiments, thereducing agent converts an amide to an amine. Numerous reducing agentsare known in the art and can be identified by comparing redox potentialsof the reducing agent and the substance to be reduced. Typically, areducing agent has a lower reducing potential than the substance to bereduced. Methods for measuring redox potentials are well known in theart. In other embodiments, the reducing agent can be an oxo acceptor.Example reducing agents include metal hydrides such as borohydrides(e.g., NaBH₄, LiBH₄, NaBH₃CN) and aluminum hydrides (e.g., LiAlH₄)including, for example, C₁-C₈ alkyl aluminum hydrides, C₂-C₁₆ dialkylaluminum hydrides, alkoxy aluminum hydrides (e.g., mono-, di-, andtrialkoxy aluminum hydrides). Other suitable reducing agents includeboranes such as BH₃ or B₂H₆ and adducts thereof. Example borane adductsinclude, for example, dialkylsulfide boranes (e.g., BH₃:CH₃SCH₃), amineboranes (e.g., BH₃:triethylamine), dialkyl ether boranes (e.g.,BH₃:diethyl ether), cyclic ether boranes (e.g., BH₃:tetrahydrofuran),C₁-C₈ alkyl boranes, C₂-C₁₆ dialkyl boranes, C₃-C₂₄ trialkyl boranes(e.g., 9-borabicyclo[3.3.1]nonane), cyclic boranes (e.g., borolanes),and the like. Further example reducing agents include Red-Al and H₂optionally in the presence of catalyst such as Pd/C.

As used herein, the term “cyclizing reagent” refers to any chemicalreagent that can be used in a reaction to cyclize a linear or branchedmolecule or portion of a molecule. In some embodiments according to thepresent invention, cyclization of a linear or branched moiety attachedto an aryl compound can be carried out using, for example, a Lewis acid.As is known in the art, a Lewis acid includes a molecule that can accepta lone pair of electrons. Example Lewis acids include hydrogen ion (aproton), boron derivatives such as BH₃ and BF₃, and aluminum derivativessuch as AlCl₃. Some example Lewis acids include C₁-C₈ alkyl aluminumhalide (e.g., methyl aluminum chloride, ethyl aluminum chloride, etc.),a C₂-C₁₆ dialkyl aluminum halide (e.g., dimethyl aluminum chloride,diethyl aluminum chloride, etc.), and trialkylaluminum.

In some embodiments, cyclizing can be carried out according toFriedel-Crafts alkylation chemistry which is known to follow the generaltransformation: ArH+RCH₂Cl→ArCH₂R (Ar is aryl and R is, for example, anyalkyl, amino, or other group) in the presence of a reagent such as aLewis acid. Friedel-Crafts reactions are typically carried out in thepresence of AlCl₃ and optionally at elevated temperatures. SuitableLewis acids include boron-containing reagents and aluminum containingreagents. Example boron-containing reagents include BH₃, BF₃ and adductsthereof (e.g., BF₃:TBME and BF₃:OEt₂). Example aluminum-containingreagents include alkyl aluminum halides, dialkyl aluminum halides,trialkyl aluminum, and aluminum halides (e.g., AlCl₃ and AlBr₃). Othersuitable cyclizing reagents include, for example, acids such as sulfuricacid, sulfonic acids (e.g., CF₃SO₃H, CH₃SO₃H, pTSA), phosphoric acids,polyphosphoric acids (e.g., H₃PO₄/P₂O₅), and the like. Additionalsuitable Friedel-Crafts alkylation catalysts include FeCl₃, TiCl₄,ZrCl₄, and ZnCl₄.

As used herein, the term “halogenating/sulfonating reagent” refers toany chemical reagent that can be used to replace hydrogen or a chemicalsubstituent on a molecule with a leaving group such as a halogen moietyor sulfonate moiety (e.g., alkyl sulfonate, mesylate, tosylate, etc.).In some embodiments, the halogenating/sulfonating reagent replaces ahydroxyl with a halogen moiety or sulfonate moiety. Examplehalogenating/sulfonating reagents include phosphorous trihalides (e.g.,PBr₃), phosphorous pentahalides, phosphorous oxyhalides, thionyl halides(e.g., SOBr₂), and the like. Other halogenating/sulfonating reagentsinclude N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin,pyridinium tribromide (pyrHBr₃), diethylaminosulfur trifluoride (DAST),N-fluorobenzenesulfonimide, and the like. Furtherhalogenating/sulfonating reagents include sulfonyl halides such as mesylchloride, tosyl chloride, and the like.

As used herein, the term “leaving group” refers to a moiety that can bedisplaced by another moiety, such as by nucleophilic attack, during achemical reaction. Leaving groups are well known in the art and include,for example, halogen, hydroxy, alkoxy, —O(CO)R⁶, —SO₂—R^(b), and—OSi(R^(c))₃ wherein R^(a) can be C₁-C₈ alkyl, C₃-C₇ cycloalkyl, aryl,heteroaryl, or heterocycloalkyl, wherein R^(b) can be C₁-C₈ alkyl, aryl(optionally substituted by one or more halo, cyano, nitro, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkoxy), or heteroaryl(optionally substituted by one or more halo, cyano, nitro, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄ haloalkoxy), and wherein R^(c)can be C₁-C₈ alkyl. Example leaving groups include chloro, bromo, iodo,mesylate, tosylate, trimethylsilyl, and the like.

As used herein, the terms “resolving” and “resolution” are used as knownin the art and generally refer to the separation of a mixture of isomerssuch as stereoisomers (e.g., optical isomers such as enantiomers ordiastereomers). Resolving can include processes that can increase theproportion of one stereoisomer over another in a mixture ofstereoisomers. A mixture of stereoisomers having a greater proportion ofa first steroisomer over a further stereoisomer can be said to be“enriched” in the first stereo isomer.

As used herein, the term “precipitating” is used as known in the art andgenerally refers to the formation of solid (e.g., precipitate) from asolution in which the solid is dissolved. The solid can be amorphous,crystalline, or a mixture thereof. Methods of precipitation are wellknown in the art and include, for example, increasing the proportion ofsolvent in which a solute is insoluble, decreasing temperature,chemically transforming the solute such that it becomes no longersoluble in its solvent, and the like. Precipitation can be used toincrease the proportion of a stereoisomer in a mixture of stereoisomers.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatograpy (HPLC) or thin layerchromatography.

In some embodiments, preparation of compounds can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Green and Wuts, et al.,Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, 1999,which is incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected. In some embodiments, reactionscan be carried out in the absence of solvent, such as when at least oneof the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane, tetrachloroethylene, trichloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,2-chloropropane, α,α,α-trifluorotoluene, 1,2-dichloroethane,1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene,o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane,chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride,dichlorofluoromethane, chlorodifluoromethane, trifluoromethane,1,2-dichlorotetrafluorethane and hexafluoroethane.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, triethylene glycol dimethyl ether,anisole, or t-butyl methyl ether.

Suitable protic solvents can include, by way of example and withoutlimitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,2-methoxyethanol, l-butanol, 2-butanol, i-butyl alcohol, t-butylalcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,phenol, or glycerol.

Suitable aprotic solvents can include, by way of example and withoutlimitation, tetrahydrofuran (THF), dimethylformamide (DMF),dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NM),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, or hexamethylphosphoramide.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

Supercritical carbon dioxide can also be used as a solvent.

The reactions of the processes described herein can be carried out atappropriate temperatures which can be readily determined by the skilledartisan. Reaction temperatures will depend on, for example, the meltingand boiling points of the reagents and solvent, if present; thethermodynamics of the reaction, (e.g., vigorously exothermic reactionsmay need to be carried out at reduced temperatures); and the kinetics ofthe reaction (e.g., a high activation energy barrier may need elevatedtemperatures). “Elevated temperature” refers to temperatures above roomtemperature (about 20° C.) and “reduced temperature” refers totemperatures below room temperature.

The reactions of the processes described herein can be carried out inair or under an inert atomosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto the skilled artisan.

In some embodiments, preparation of compounds can involve the additionof acids or bases to effect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids. Inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andnitric acid. Organic acids include formic acid, acetic acid, propionicacid, butanoic acid, methanesulfonic acid, p-toluene sulfonic acid,benzenesulfonic acid, trifluoroacetic acid, propiolic acid, butyricacid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid,heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.Some example strong bases include, but are not limited to, hydroxide,alkoxides, metal amides, metal hydrides, metal dialkylamides andarylamines, wherein; alkoxides include lithium, sodium and potassiumsalts of methyl, ethyl and t-butyl oxides; metal amides include sodiumamide, potassium amide and lithium amide; metal hydrides include sodiumhydride, potassium hydride and lithium hydride; and metal dialkylamidesinclude sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis.

The processes described herein can be stereoselective such that anygiven reaction starting with one or more chiral reagents enriched in onestereoisomer forms a product that is also enriched in one stereoisomer.The reaction can be conducted such that the product of the reactionsubstantially retains one or more chiral centers present in the startingmaterials. The reaction can also be conducted such that the product ofthe reaction contains a chiral center that is substantially invertedrelative to a corresponding chiral center present in the startingmaterials.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, noresphedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, camphoric acid,α-methoxy-α-trifluoromethylphenylacetic acid (MTPA or Mosher's acid),pyrrolidone-5-carboxylic acid, di-O-isopropylene-keto-glutamic acid,di-toluoyl-tartaric acid, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

The present invention also includes salt forms of the compoundsdescribed herein. Examples of salts (or salt forms) include, but are notlimited to, mineral or organic acid salts of basic residues such asamines, alkali or organic salts of acidic residues such as carboxylicacids, and the like. Generally, the salt forms can be prepared byreacting the free base or acid with stoichiometric amounts or with anexcess of the desired salt-forming inorganic or organic acid or base ina suitable solvent or various combinations of solvents. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosureof which is hereby incorporated by reference in its entirety.

Upon carrying out preparation of compounds according to the processesdescribed herein, the usual isolation and purification operations suchas concentration, filtration, extraction, solid-phase extraction,recrystallization, chromatography, and the like may be used, to isolatethe desired products.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES Example 1 Preparation of2-(4-chlorophenyl)ethyl-N-2-chloropropionamide

To a 1-liter, 3-necked round bottom flask under argon balloon equippedwith reflux condenser and addition funnel, were added sequentially2-(4-chlorophenyl) ethylamine (30 g, 193 mmol), 400 mL acetonitrile,triethylamine (19.5 g, 193 mmol) and 80 mL acetonitrile. The clearcolorless solution was stirred and cooled to 0° C. 2-Chloropropionylchloride (24.5 g, 193 mmol, distilled) in 5 mL acetonitrile was slowlyadded over 20 minutes to evolution of white gas, formation of whiteprecipitate, and color change of reaction mixture to slight yellow. Anadditional 10 mL of acetonitrile was used to rinse the addition funnel.The mixture was stirred at 0° C. for 30 minutes and then warmed to roomtemperature and stirred vigorously for an additional one hour. Theyellow reaction mixture was concentrated on the rotary evaporator to asolid containing triethylamine hydrochloride (76.36 grams). Thismaterial was taken up in 100 mL ethylacetate and 200 mL water, andstirred vigorously. The layers were separated and the aqueous layer wasextracted with an additional 100 mL ethylacetate. The combined organiclayers were washed twice with 25 mL of saturated brine, dried overmagnesium sulfate, filtered, and concentrated to a light tan solid (41.6grams, 88%). TLC in ethylacetate-hexane, 8:2 showed a major spottwo-thirds of the way up the plate and a small spot at the baseline.Baseline spot was removed as follows: This material was taken up in 40mL of ethylacetate and hexane was added until the solution becamecloudy. Cooling to 0° C. produced a white crystalline solid (40.2 grams,85% yield). The product is a known compound (Hasan et al., Indian J.Chem., 1971, 9(9), 1022) with CAS Registry No. 34164-14-2.

LC/MS gave product 2.45 minute; 246.1 M⁺+H⁺.

¹H NMR (CDCl₃): δ 7.2 (dd, 4H, Ar), 6.7 (br S, 1H, NM, 4.38 (q, 1H,CHCH₃), 3.5 (q, 2H, ArCH₂CH2NH), 2.8 (t, 2H, ArCH₂), 1.7 (d, 3H, CH₃).

¹³C NMR (CDCl₃): 169 (1C, C═O), 136 (1C, Ar—Cl), 132 (1C, Ar), 130 (2C,Ar), 128 (2C, Ar), 56 (1C, CHCl), 40 (1C, CHN), 34 (1C, CHAr), 22 (1C,CH₃).

Example 2 Preparation of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one

2-(4-Chlorophenyl)ethyl-N-2-chloropropionamide (10 g, 40.6 mmol) ofExample 1 and aluminum chloride (16 g, 119.9 mmol) were added to a cleandry 100 mL round bottom flask equipped with an argon balloon, stirringapparatus, and heating apparatus. The white solid melted to a tan oilwith bubbling at 91° C. (Note: if impure starting materials are used, ablack tar can result but clean product can still be isolated). Themixture was heated and stirred at 150° C. for 12 hours. (Note: The timeis dependent on the reaction scale and can easily be followed by LC/MS;higher temperatures can be used for shorter time periods. E.g., a 1 gramsample was complete in 5 hours.) The reaction can be followed by LC/MSwith the starting material at 2.45 minutes (246.1 M⁺+H⁺), the product at2.24 minutes (209.6 M⁺+H⁺) on a 5 minute reaction time from 5-95%w/0.01% TFA in water/MeCN (50:50).

After cooling to room temperature, the reaction mixture was quenchedwith slow addition of 10 mL of MeOH followed by 5 mL of 5% HCl in waterand 5 mL of ethyl acetate. After separation of the resulting layers, theaqueous layer was extracted a second time with 10 mL of ethyl acetate.The combined organic layers were dried over magnesium sulfate, filtered,and concentrated to a tan solid (6.78 grams, 80% yield). LC/MS showedone peak, at 2.2 min and 209.6 MI. This material was taken up in ethylacetate, filtered through celite and Kieselgel 60 (0.5 inch plug on a 60mL Buchner funnel) and the filtrate was recrystallized from hexane/ethylacetate to give final product (4.61 grams, 54% yield).

¹H NMR (CDCl₃): 7.3-7.1 (m, 3H, Ar), 5.6 (br S, 1H, NH), 4.23 (q, 1H,CHCH₃), 3.8 (m, 1H, ArCH₂CH ₂NH), 3.49 (m, 1H, ArCH₂CH ₂NH), 3.48 (m,1H, ArCH ₂CH₂NH), 3.05 (m, 1H, ArCH ₂CH₂NH), 1.6 (d, 3H, CH₂).

¹³C NMR (CDCl₃): 178 (1C, C═O), 139 (1C, Ar), 135 (1C, Ar), 130, 129(2C, Ar), 126 (2C, Ar), 42 (1C, C), 40 (1C, CHN), 33 (1C, CHAr), 14 (1C,CH₃).

Example 3 Preparation of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Procedure A

HPLC purified 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one(150 mg, 0.716 mmol) of Example 2 was added to a 50 mL round bottomflask with 2M borane-tetrahydrofuran solution (2 mL, 2.15 mmol). Themixture was stirred 10 hours at room temperature under an argon balloon.LC/MS showed the desired product as the major peak with approximately 5%of starting material still present. The reaction mixture was quenchedwith 5 mL methanol and the solvents were removed on the rotaryevaporator. This procedure was repeated with methanol addition andevaporation. The mixture was evaporated on the rotary evaporatorfollowed by 2 hours in vacuo to give the product as a white solid (117mg, 70% yield).

NMR, LC/MS and other analytical data are provided below.

Procedure B

Recrystallized8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (137 mg,0.653 mmol) was added to a 50 mL round bottom flask with stirring undernitrogen gas. To the flask was slowly added borane-tetrahydrofuransolution (1M, 10 mL) followed by boron trifluoride TBME solution (1 mL,8.85 mmol) with vigorous gas evolution. The mixture was stirred 6 hoursat room temperature under nitrogen gas. LC/MS showed the desiredproduct. The reaction mixture was quenched with 5 mL methanol and 3 mLconc. HCl and the solvents were removed on the rotary evaporator. Thisprocedure was repeated with methanol and HCl addition and evaporation.The mixture was evaporated on the rotary evaporator followed by 2 hourson the pump to dryness to give8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine hydrochloride (106mg, 70% yield).

¹H NMR (CDCl₃): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m,2H), 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).

LC/MS: 1.41 minute, 196.1 M+H⁺and 139 major fragment. No impurities wereobserved.

Example 4 Preparation of L-(+)-tartaric acid salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a clean, dry 50 mL round bottom flask were added 11.5 g (0.06 mol) of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine from Example 3 to2.23 g (0.015 mol) of L-(+)-tartaric acid. The suspension was dilutedwith 56 g of tert-butanol and 6.5 mL of H₂O. The mixture was heated toreflux (75-78° C.) and stirred for 10 min to obtain a colorlesssolution. The solution was slowly cooled down to room temperature(during 1 h) and stirred for 3 h at room temperature. The suspension wasfiltered and the residue was washed twice with acetone (10 mL). Theproduct was dried under reduced pressure (50 mbar) at 60° C. to yield6.3 g of the tartrate salt (ee=80). This tartrate salt was added to 56 gof tert-butanol and 6.5 mL of H₂O. The resulting suspension was heatedto reflux and 1 to 2 g of H₂O was added to obtain a colorless solution.The solution was slowly cooled down to room temperature (over the courseof 1 h) and stirred for 3 h at room temperature. The suspension wasfiltered and the residue was washed twice with acetone (10 mL). Theproduct was dried under reduced pressure (50 mbar) at 60° C. to produce4.9 g (48% yield) of product (ee>98.9).

If the ee value of the product obtained is not satisfactory, anadditional recrystallization can be carried out as described. Eitherenantiomer can be synthesized in high ee utilizing this method.

Example 5 Conversion of Salt Form to Free Amine

The L-tartaric acid salt of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (300 mg, 0.87mmol) from Example 4 was added to a 25 mL round bottom flask with 50%sodium hydroxide solution (114 μL, 2.17 mmol) with an added 2 mL ofwater. The mixture was stirred 3 minutes at room temperature. Thesolution was extracted with methylene chloride (5 mL) twice. Thecombined organic extracts were washed with water (5 mL) and evaporatedto dryness on the pump to get free amine (220 mg crude weight). LC/MS196 (M+H).

Example 6 Preparation of 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride

To a dry 100-milliliter, round bottom flask under nitrogen with stirringwas added 2-(4-chlorophenyl)ethyl-N-2-chloropropionylamide (8.8 g, 35.8mmol) followed by borane in THF (1.8 M, 70 mL, 140 mmol) over 10 minutes(gas evolution and solid becomes solubilized). After the addition wascomplete, boron trifluoride in tert-butyl methyl ether (8 mL, 70.8 mmol)was added over 10 minutes with more gas evolution. After 4 hours, LC/MSshowed complete reaction. The reaction mixture was quenched with 20 mLof conc. HCL (37%) with additional of gas evolution. The reactionmixture was stirred at 40° C. for 2 hours, cooled to room temperatureand evaporated. Then, the white slurry was taken up in 40 mL ethylacetate and 20 mL of 2.5 M NaOH to make a yellow solution over a whiteslurry. The yellow organic layer was washed with brine, dried overmagnesium sulfate, filtered and evaporated to give 12.2 grams of whiteto yellow solid. This solid was recrystallized from ethyl acetate/hexanein two crops to give 6.7 grams of white solid product (80% yield).

¹H NMR (DMSO-d6): 9.0 (br s, 2 H, NH, HCl), 7.2 (d, 2H, J=8 Hz), 7.05(d, 2H, J=8 Hz), 4.5 (m, 1H), 3.2 (m, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 1.5(d, 3H, J=7 Hz).

LC/MS: 1.71 minute, 232.1 M +H⁺ and 139 major fragment. Minor impurityobserved at 2.46 min with 321 and 139 peaks.

Example 7 Preparation of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Small Scale

2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride (1 g, 4.3 mmol) of Example6 was reacted with aluminum chloride (3 g, 22 mmol) in a dry 50 mL roundbottom flask under nitrogen gas in an oil bath at 120° C. wth stirring.Analysis by LC/MS showed complete reaction in two hours. After coolingthe resulting black oil to room temperature, 20 mL ethyl acetate and 20mL of pH 6 water were added. After 30 min of vigorous stirring themixture was solubilized to a clear colorless upper organic layer and abrown clear lower aqueous layer. After separation of the layers, theaqueous layer was extracted two additional times with 20 mL ethylacetate. The combined organic layers were dried over magnesium sulfate,filtered and evaporated to give 0.55 grams (55% yield) of a white toslightly yellow solid containing the HCl salt. This material was foundto be very hygroscopic. The remaining aqueous layer (pH 6) was broughtto pH 15 by addition of 5 grams of NaOH pellets. The aqueous layerbecame a thick white emulsion. Three times 40 mL of ethyl acetate wereadded to the thick white emulsion and decanted off. The combined organiclayers were dried over magnesium sulfate, filtered and evaporated togive 0.3 g (36%) of a brown oil containing free amine. The combinedyield was 91%.

¹H NMR (CDCl₃): 7.2 (d, 1H, J=2.5 Hz), 7.15 (dd, 1H, J=2.5, 8 Hz), 7.05(d, 1 H, J=8 Hz), 3.6 (m, 2 H), 3.5 (m, 2H), 3.1 (m, 2 H), 2.9 (m, 2 H),1.5 (d, 3H, J=7 Hz).

¹³C NMR (CDCl₃): 144, 136, 133, 131, 127 (2), 51, 45,32,30, 17.

LC/MS: 1.41 minute, 196.1 M+H⁺ and 139 major fragment. No impuritiesobserved.

Large Scale

2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride (49.24 g,179.92 mmol) andaluminum trichloride (34.79 g, 260.89 mmol) were added to a flask undera nitrogen atmosphere. To this solid mixture, 1,2-dichlorobenzene(139.31 g) was added resulting in a suspension which was then heated to120° C. which was associated with evolution of hydrogen chloride gas,which was neutralized in a sodium hydroxide filled gas scrubber. Thereaction mixture became a yellow to brown solution which was heated at120° C. for a total of 12 hours. At the end of this time HPLC analysisindicated that the ratio of product to starting material was greaterthan 99:1 The reaction solution was cooled to 20 to 30° C. and addeddropwise to a mixture of sodium hydroxide solution (176.0 g, 1320 mmol)approx. 30%, water (79.5 g), and cyclohexane (176 g), so that theinternal temperature did not exceed 50° C. The layers were separated andthe lower aqueous layer was extracted with cyclohexane (74 g). Thecombined organic layers were extracted with a solution of aq.hydrochloric acid (22.76 g, 231 mmol) 36/38% and water (68.23 g). Theorganic layer was extracted with water (45.47 g). The combined aqueouslayers were washed with cyclohexane (37 g). To the aqueous layer wasadded sodium hydroxide (40.08 g, 301 mmol) solution approx. 30% andcyclohexane (100 g). The aqueous layer was extracted with cyclohexane(100 g). The combined organic layers were concentrated at 40° C. to 60°C. and a final vacuum of 30 mbar to give 36.79 g, of a yellow oil. HPLCanalysis indicated that the product had a purity of 85.45%, thus givinga corrected yield of 89.29%.

Example 8 Preparation of 2-(4chlorophenyl)ethylbromide

2-(4-Chlorophenyl)ethylbromide was prepared according to Robert, et al.,J. Org. Chem., 1987, 52, 5594).

Small Scale

To a 100-mililiter, round bottom flask under nitrogen containing2-(4-chlorophenyl)ethanol (10 g, 193 mmol) was added phosphoroustribromide (19g, 193 mmol) via syringe while cooling 0° C. After theaddition was complete, the ice bath was removed and the mixture washeated to 95° C. for two hours. The reaction mixture was quenched withslow addition of water in an ice bath. The material was taken up in 30mL of methylene chloride, the layers were separated, and the organiclayer was dried over magnesium sulfate, filtered, and evaporated todryness to obtain 13.8 grams of clear oil (98% yield). LC/MS and protonNMR were as expected. ¹H-NMR: 3.10 t, 3.51 t, 7.11 d, 7.26 d.

Large Scale

To 171.05 g (1.092 mol) of 2-(4-chlorophenyl)ethanol was added dropwise147.82 g (0.546 mol) of phosphorous tribromide over 3 hours and at atemperature of 0° C. The mixture was stirred at 0° C. for 15 min, atroom temperature for 2 h, and then at 100° C. for 2 h, cooled to 0° C.,hydrolized by dropwise addition of 400.0 g of water and diluted with400.0 g of tert-butyl methyl ether. The organic layer was separated andwashed with 100.0 g of water. The solvent was distilled off underreduced pressure to yield a colorless liquid. Yield: 95% (based onpurity). Purity: 96%. Volume yield (reaction): 100.0%. Volume yield(extraction): 18.0%. ¹H-NMR: 3.10 t, 3.51 t, 7.11 d, 7.26 d.

Example 9 Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propanol

Small Scale

To 2-(4-chlorophenyl)ethylbromide (0.5 g, 2.28 mmol, from Example 8) ina 25 mL round bottom flask were added 1-amino-2-propanol (1.7 g, 22.8mmol) dropwise via syringe at 95° C. The addition was carried out overone hour and the reaction mixture was stirred at 95° C. for anadditional two hours. Then, the reaction mixture was cooled to roomtemperature and 3 mL of water were added, 10 mL of ethylacetate wereadded, and the organic layer was separated, dried over magnesiumsulfate, filtered and concentrated to obtain 0.453 g of yellow solid(93% yield). LC/MS and proton NMR were as expected.

Large Scale

To 821.25 g (10.93 mol) of 1-amino-2-propanol was added dropwise 240.01g (1.093 mol) of 2-(4-chlorophenyl)ethylbromide during 3 hours and atemperature of 90-100° C. The mixture is stirred at 90-100° C. forfurther 1 h, cooled to room temperature, and diluted with 859.6 g ofwater. The water layer was extracted three times with 150.0 g oftert-butyl methyl ether. The combined organic phases were washed with100.0 g of water, the solvent was distilled off at a temperature of 60°C. and reduced pressure to yield a colorless solid with a melting pointof 68-70° C. Yield: 87% (based on purity). Purity: 99%. Volume yield(reaction): 21%. Volume yield (extraction): 12%. ¹H-NMR: 1.12 d, 2.42dd, 2.5-2.9 m, 2.62 d, 2.82 t, 3.75 m, 7.11 d, 7.23 d.

Example 10 Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide

This preparation was based on Nagle et al., Tetrahedron Letters, 2000,41, 3011.

Small Scale

2-(4-Chlorophenyl)-N-ethyl-N-2-propanol (453 mg, 2.12 mmol, see Example9) was dissolved in 1.5, mL methylene chloride and dimethyl formamide(0.77 mL) was added to the solution. The reaction mixture was cooled toat 0° C. and thionyl bromide (0.23 mL, 3.0 mmol) was added dropwise. Thereaction was then stirred at room temperature for two hours. The productprecipitated. The mixture was cooled to 0° C. and the precipitate wasfiltered and washed with cold methylene chloride to obtain 350 mg ofwhite solid. A second crop was obtained by concentrating, retaking up inmethylene chloride, and cooling to obtain an additional 72 mg of product(56% yield).

¹H NMR (DMSO-d₆): 8.7 (br s, 1H), 8.6 (br s, 1H), 7.2 (d, 2H, J=8 Hz),7.1 (d, 2 H, J=8 Hz), 4.32 (m, 1H), 3.51 (br m, 1H), 3.28 (br m, 1H),3.03 (m, 2H), 2.82 (m, 2H), 1.5 (d, 3H, J=7 Hz).

¹³C NMR (DMSO-d₆): 136, 131, 130 (2), 128 (2), 53, 47, 44, 30, 23.

LC/MS: 1.56 min, 278 M+H⁺ (—HBr) and 139 major fragment.

Large Scale

194.0 g (0.91 mol) of 2-4-chlorophenyl)-N-ethyl-N-2-propanol weredissolved in 1000.0 g of CH₂Cl₂. Then 31.17 g (0.46 mol) ofN,N-Dimethylformamide were added and the clear solution was cooled downto 0° C. At this temperature, 264.3 g (1.4 mol) of thionyl bromide wereadded within 1 h. After complete addition, the reaction mixture wasallowed to warm up to room temperature and stirred for further 12 h,while precipitation of the product occurred. The reaction mixture wascooled to 0° C. and the precipitate was filtered off and washed with500.0 g of ice-cold CH₂Cl₂, dried at 80° C. under reduced pressure toobtain an off-white powder with a melting point of 194-197° C. Yield:63% (based on purity). Purity: 97%. Volume yield (reaction): 14%.¹H-NMR: 1.80 d, 3.05 m, 3.15 m, 3.45 m, 4.59 m, 7.15 d, 7.40 d, 8.95 s.

Example 11 Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propylchloride

267 g (125 mmol) of 2-(4-chlorophenyl)-N-ethyl-N-2-propanol was dilutedwith 364 g of toluene and warmed to 40° C. 19.30 g, 222 mmoldimethylacetamide were added and following this 111.83 g 940 mmolthionyl chloride was added dropwise so that the internal temperature waskept between 40 and 60° C. The resulting thick suspension was stirredfor 2 to 3 hours at 60 to 65° C. The suspension was filtered and washedwith 335 g of toluene via the reactor. The resulting 397.1 g of a browncrude product was suspended in 326 g of isopropanol and 35.2 g of water,and heated to approx. 80 to 85° C. to reflux forming a clear brownsolution. The solution was then cooled over 3 to 12 h to 0 to 5° C. andstirred for at least 1 hour at 0 to 5° C., before being centrifuged. Thewet product was washed with 146 g of isopropanol in several parts viathe reactor and with 100 g of isopropanol directly over the filter cake(when the material is still colored, the amount of isopropanol can beincreased until colourless material is obtained). About 790 g of motherliquid with pH =0 was also formed. 157.93 g of a white to lightly beigewet product was yielded, which was dried at 70° C. in vacuum at 30 mbar.Yield: 113.42 g (99.53 percent by weight).

Example 12 Preparation of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Small scale

To 2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide (0.343 g, 0.959 mmol,see Example 10) in a 50 mL round bottom flask was added aluminumchloride (0.192 g, 1.44 mmol). The two solids were heated at 140° C. for4 hours and then cooled to 90° C. Toluene (350 microliters) was addedand the reaction mixture was cooled to room temperature. Water (350microliters) was added as well as I gram of ice. The mixture was stirredfor 15 minutes then sodium hydroxide solution (350 microliters of asolution made up of 2 g of NaOH in 6 g water) was added. The reactionmixture was extracted three times with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate and concentrated togive 218 mg of a dark yellow oil product (90% yield).

Attempted distillation of the oil product at 115-180° C. and 0.1 torrcaused decomposition and dimerization.

LC/MS and proton NMR are as expected.

Large Scale

A 750 mL reaction vessel was charged with2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide (240 g, 0.67 mol) to whichaluminum chloride (134 g, 1.01 mol) and 1,2-dichlorobenzene (480 g) wereadded. The resulting suspension was heated to 138-142 IC (yellowsolution) and HBr-gas evolved (neutralized with sodium hydroxidesolution). The reaction was stirred for 8-12 hours (monitored by HPLC).The reaction was cooled to 20-30° C. and transferred to a droppingfunnel. Extraction mixture containing water (300 g), 30% sodiumhydroxide solution (670 g), and cyclohexane (670 g) was added to thereaction vessel. The reaction solution was added portionwise to theextraction mixture while cooling keeping the temperature below 50° C.The resulting layers were separated and the aqueous phase was extractedwith cyclohexane (144 g). The organic layers were combined and extractedwith a solution of HCl (pH of the water layer was <2). The organic layerwas extracted once more with water. The combined water layers werewashed with cyclohexane. A 30% sodium hydroxide solution (100 g) wasthen added (pH of the water layer was >13). The water layer was firstextracted with cyclohexane (720 g) and then with further cyclohexane(144 g). The combined organic layers were dried over sodium sulfate. Thesodium sulfate was filtered out and the filtrate was evaporated underreduced pressure at a temperature of 45-50° C. Crude product wasobtained as a glutinous oil (134.42 g).

Example 13 Large Scale Preparation of L-(+)-tartaric acid salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Crude product (134.32 g) of the large scale synthesis of Example 12 wasdissolved in tert-butanol (480 g). An aqueous solution of L-(+)-tartaricacid (21 g of acid in 30 g of water) and seed crystals were added. Thesolution was stirred at 15-25° C. overnight until crystals formed. Theresulting suspension was filtered and the precipitate washed withacetone. EE was 68.1% (HPLC). The precipitate was then refluxed inadditional tert-butanol (480 g) and water (10 g). Water (80 g) was addeduntil the precipitate dissolved completely and then the solution wascooled to 15-25° C. and stirred overnight. The resulting precipitate wasfiltered out and washed with acetone. EE was 96.8% (HPLC). Theprecipitate was again refluxed in additional tert-butanol (480 g) andstirred for 1 hour at reflux. The resulting suspension was cooled to15-25° C. and stirred overnight. The resulting precipitate was filteredout and washed with acetone. EE was 98.7% (HPLC) and the product wasdried under vacuum at 60° C. Yield was 34.96 g.

Example 14 Preparation of Hydrochloric Acid Salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a clean, dry 25 mL round bottom flask were added(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free amine(220 mg), 3 ML methylene chloride, and 1.74 mL of 1M HCl in ether. Themixture was stirred for 5 minutes at room temperature. The solvent wasremoved under reduced pressure to give a white solid, the HCl salt. Thesalt was re-dissolved in methylene chloride (3 mL) and an additional1.74 mL of 1 M HCl was added and the solution was again stirred at roomtemperature for 5 minutes. The solvent was removed under reducedpressure to give the desired HCl salt of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine (190 mg crudeweight, 95% yield). NMR data was consistent with the desired product.

¹H NMR (CDCl₃): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m,2H, 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication is incorporated herein by reference in its entirety.

1. A process for preparing a compound of Formula V:

or salt thereof, wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl,—CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), orC₁-C₄ haloalkyl; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,C(O)NH-alkyl, hydroxyalkyl, NR¹⁰OR¹¹, CN, NO₂, heterocycloalkyl, aryl,or heteroaryl, wherein said aryl and heteroaryl can be substituted withone or more substituents selected from C₁-C₈ alkyl, halo, C₁-C₈haloalkyl, and alkoxy; or R⁴ and R⁵ together with the atoms to whichthey are attached form a 5- or 6-member heterocyclic ring having one Oatom; R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl,alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, orhydroxyalkyl, or R^(8a) and R^(8b) together with the carbon atom towhich they are attached form a C₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl,aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; and R¹⁰ and R¹¹are each, independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl,heteroarylalkyl, or allyl, or R¹⁰ and R¹¹ together with the N atom towhich they are attached form a heterocyclic ring; comprising: a)reacting a compound of Formula XII:

with a halogenating/sulfonating reagent for a time and under conditionssuitable for forming a compound of Formula XI:

wherein X¹ is a leaving group; b) reacting said compound of Formula XIwith a compound of Formula:

or salt thereof, for a time and under conditions suitable for forming acompound of Formula X:

or salt thereof; c) reacting said compound of Formula X with a furtherhalogenating/sulfonating reagent for a time and under conditionssuitable for forming a compound of Formula IX:

or salt thereof; wherein X² is halo or SO₂R″ and R″ is C₁-C₈ alkyl,aryl, or heteroaryl each optionally substituted by one or more halo,cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄haloalkoxy; and d) reacting said compound of Formula IX with a cyclizingreagent for a time and under conditions suitable for forming saidcompound of Formula V.
 2. The process of claim 1 wherein said cyclizingreagent is AlCl₃.
 3. The process of claim 1 wherein saidhalogenating/sulfonating reagent is PBr₃ or PCl₃.
 4. The process ofclaim 1 wherein said further halogenating/sulfonating reagent is SOBr₂or SOCl₂.
 5. The process of claim 1 wherein X² is Cl.
 6. The process ofclaim 1 wherein X¹ is Br.
 7. The process of claim 1, 5, or 6 wherein R¹is H, R² is Me, R³ is H, R⁴ is Cl, R⁵ is H, R⁶ is H, R⁸a is H, and R⁸bis H.
 8. A process for preparing a compound of Formula V:

or salt thereof, wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl,—CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), orC₁-C₄ haloalkyl; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,C(O)NH-alkyl, hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, orheteroaryl, wherein said aryl and heteroaryl can be substituted with oneor more substituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl,and alkoxy; or R⁴ and R⁵ together with the atoms to which they areattached form a 5- or 6-member heterocyclic ring having one O atom;R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b p)together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl,aryl, heteroaryl, heteroarylalkyl, or allyl; and R¹⁰ and R¹¹ are each,independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl,or allyl, or R¹⁰ and R¹¹ together with the N atom to which they areattached form a heterocyclic ring; comprising: a) reacting a compound ofFormula XI:

wherein X¹ is a leaving group, with a compound of Formula:

or salt thereof, for a time and under conditions suitable for forming acompound of Formula X:

or salt thereof; b) reacting said compound of Formula X with ahalogenating/sulfonating reagent for a time and under conditionssuitable for forming a compound of Formula IX:

or salt thereof; wherein X² is halo or SO₂R″ and R″ is C₁-C₈ alkyl,aryl, or heteroaryl each optionally substituted by one or more halo,cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄haloalkoxy; and c) reacting said compound of Formula IX with a cyclizingreagent for a time and under conditions suitable for forming saidcompound of Formula V.
 9. The process of claim 8 wherein said cyclizingreagent is AlCl₃.
 10. The process of claim 8 wherein saidhalogenating/sulfonating reagent is SOBr₂ or SOCl₂.
 11. The process ofclaim 8 wherein X² is Cl.
 12. The process of claim 8 wherein X¹ is Br.13. The process of claim 8, 11, or 12 wherein R¹ is H, R²is Me, R³is H,R⁴ is Cl, R⁵ is H, R⁶ is H, R⁸a is H, and R⁸b is H.
 14. A process forpreparing a compound of Formula V:

or salt thereof, wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl,—CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), orC₁-C₄ haloalkyl; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,C(O)NH-alkyl, hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, orheteroaryl, wherein said aryl and heteroaryl can be substituted with oneor more substituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl,and alkoxy; or R⁴ and R⁵ together with the atoms to which they areattached form a 5- or 6-member heterocyclic ring having one O atom;R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl,aryl, heteroaryl, heteroarylalkyl, or allyl; and R¹⁰ and R¹¹ are each,independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl,or allyl, or R¹⁰ and R¹¹ together with the N atom to which they areattached form a heterocyclic ring; comprising: a) reacting a compound ofFormula X:

or salt thereof; with a halogenating/sulfonating reagent for a time andunder conditions suitable for forming a compound of Formula IX:

or salt thereof; wherein X² is halo or SO₂R″ and R″ is C₁-C₈ alkyl,aryl, or heteroaryl each optionally substituted by one or more halo,cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄haloalkoxy; and b) reacting said compound of Formula IX with a cyclizingreagent for a time and under conditions suitable for forming saidcompound of Formula V.
 15. The process of claim 14 wherein saidcyclizing reagent is AlCl₃.
 16. The process of claim 14 wherein saidreacting of step (b) is carried out in the presence of1,2-dichlorobenzene.
 17. The process of claim 14 wherein saidhalogenating/sulfonating reagent is SOBr₂ or SOCl₂.
 18. The process ofclaim 14 wherein X² is Cl.
 19. The process of claim 14 wherein saidreacting of step (a) is carried out in the presence of solvent.
 20. Theprocess of claim 19 wherein said solvent comprises dimethylformamide ortoluene.
 21. The process of claim 14 wherein R¹ is H, R² is Me, R³ is H,R⁴ is Cl, R⁵ is H, R⁶ is H, R^(8a), is H, and R^(8b) is H.
 22. A processfor preparing a compound of Formula V:

or salt thereof, wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl,—CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), orC₁-C₄ haloalkyl; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,C(O)NH-alkyl, hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, orheteroaryl, wherein said aryl and heteroaryl can be substituted with oneor more substituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl,and alkoxy; or R⁴ and R⁵ together with the atoms to which they areattached form a 5- or 6-member heterocyclic ring having one O atom;R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl,aryl, heteroaryl, heteroarylalkyl, or allyl; and R¹⁰ and R¹¹ are each,independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl,or allyl, or R¹⁰ and R¹¹ together with the N atom to which they areattached form a heterocyclic ring; comprising reacting a compound ofFormula IX:

or salt thereof, wherein X² is halo or SO₂R″ and R″ is C₁-C₈ alkyl,aryl, or heteroaryl each optionally substituted by one or more halo,cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄haloalkoxy, with a cyclizing reagent for a time and under conditionssuitable for forming said compound of Formula V.
 23. The process ofclaim 22 wherein said cyclizing reagent is AlCl₃.
 24. The process ofclaim 22 wherein said reacting is carried out in the presence of1,2-dichlorobenzene.
 25. The process of claim 22 wherein said reactingis carried out at a temperature between about 100 and about 150° C. 26.The process of claim 22 wherein X² is Cl.
 27. The process of claim 22wherein R¹ is H, R² is Me, R³ is H, R⁴ is Cl, R⁵ is H, R⁶ is H, R^(8a)is H, and R^(8b) is H.
 28. A process for preparing a compound of FormulaIX:

or salt thereof, wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl,—CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), orC₁-C₄ haloalkyl; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,C(O)NH-alkyl, hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, orheteroaryl, wherein said aryl and heteroaryl can be substituted with oneor more substituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl,and alkoxy; or R⁴ and R⁵ together with the atoms to which they areattached form a 5- or 6-member heterocyclic ring having one O atom;R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl,aryl, heteroaryl, heteroarylalkyl, or allyl; R¹⁰ and R¹¹ are each,independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl,or allyl, or R¹⁰ and R¹¹ together with the N atom to which they areattached form a heterocyclic ring; and X² is halo or SO₂R″; and R″ isC₁-C₈ alkyl, aryl, or heteroaryl each optionally substituted by one ormore halo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, orC₁-C₄ haloalkoxy; comprising reacting a compound of Formula X:

or salt thereof, with a halogenating/sulfonating reagent for a time andunder conditions suitable for forming said compound of Formula XI. 29.The process of claim 28 wherein said halogenating/sulfonating reagent isSOBr₂ or SOCl₂.
 30. The process of claim 28 wherein X² is Br.
 31. Theprocess of claim 28 wherein X² is Cl.
 32. The process of claim 28wherein said reacting is carried out in the presence of a solventcomprising dimethylformamide or toluene.
 33. The process of claim 28wherein said elevated temperature is from about −40 to about 80° C. 34.The process of claim 28 wherein R¹ is H, R² is Me, R³ is H, R⁴ is Cl, R⁵is H, R⁶ is H, R^(8a) is H, and R^(8b) is H.
 35. A process for preparinga compound of Formula X:

or salt thereof, wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl,—CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), orC₁-C₄ haloalkyl; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,C(O)NH-alkyl, hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, orheteroaryl, wherein said aryl and heteroaryl can be substituted with oneor more substituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl,and alkoxy; or R⁴ and R⁵ together with the atoms to which they areattached form a 5- or 6-member heterocyclic ring having one O atom;R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl,aryl, heteroaryl, heteroarylalkyl, or allyl; and R¹⁰ and R¹¹ are each,independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl,or allyl, or R¹⁰ and R¹¹ together with the N atom to which they areattached form a heterocyclic ring; comprising reacting a compound ofFormula XI:

wherein X¹ is a leaving group, with a compound of Formula:

for a time and under conditions suitable for forming said compound ofFormula X.
 36. The process of claim 35 wherein X¹ is Br.
 37. The processof claim 35 wherein said temperature is from about 80 to about 110° C.38. The process of claim 35 wherein R¹ is H, R² is Me, R³ is H, R⁴ isCl, R⁵ is H, R⁶ is H, R^(8a) is H, and R^(8b) is H.
 39. A compound ofFormula IX or X:

or salt form thereof, wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈alkyl, —CH₂—O—(C₁-C₈ alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl),or C₁-C₄ haloalkyl; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl,C(O)NH-alkyl, hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, orheteroaryl, wherein said aryl and heteroaryl can be substituted with oneor more substituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl,and alkoxy; or R⁴ and R⁵ together with the atoms to which they areattached form a 5- or 6-member heterocyclic ring having one O atom;R^(8a) and R^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl,hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, orR^(8a) and R^(8b) together with the carbon atom to which they areattached form a C₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl,aryl, heteroaryl, heteroarylalkyl, or allyl; R¹⁰ and R¹¹ are each,independently, H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl,or allyl, or R¹⁰ and R¹¹ together with the N atom to which they areattached form a heterocyclic ring; X² is halo or SO₂R″; and R″ is C₁-C₈alkyl, aryl, or heteroaryl each optionally substituted by one or morehalo, cyano, nitro, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or C₁-C₄haloalkoxy.
 40. The compound of claim 39 wherein X² is Cl.
 41. Thecompound of claim 39 or 40 wherein R¹ is H, R² is Me, R³ is H, R⁴ is Cl,R⁵ is H, R⁶ is H, R^(8a) is H, and R^(8b) is H.
 42. A method ofresolving a mixture of compounds of Formula Va and Vb:

wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl,or CH₂OH; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl,hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰ R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom; R^(8a) andR^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl, hydroxy,C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R^(8a) andR^(8b) together with the carbon atom to which they are attached form aC₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl,heteroarylalkyl, or allyl; and R¹ and R¹¹ are each, independently, H,C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R¹⁰and R¹¹ together with the N atom to which they are attached form aheterocyclic ring; comprising: contacting said mixture of compounds witha chiral resolving acid to form chiral resolving acid salts of saidcompounds, wherein said chiral resolving acid comprises substantiallyone stereoisomer; and precipitating said chiral resolving acid salts ofsaid compounds, wherein the resulting precipitate is enriched in thechiral resolving acid salt of one of said compounds of Formula Va or Vb.43. The method of claim 42 wherein said chiral resolving acid istartaric acid.
 44. The method of claim 42 wherein said chiral resolvingacid is L-(+)-tartaric acid.
 45. The method of claim 42 wherein saidprecipitate is enriched in the chiral resolving acid salt of saidcompound of Formula Vb.
 46. The method of claim 42 or 44 wherein R¹ isH, R² is Me, R³ is H, R⁴ is Cl, R⁵ is H, R⁶is H, R^(8a) is H, and R^(8b)is H.
 47. A chiral resolving acid salt of a compound of Formula Va orVb:

wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl,or CH₂OH; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl,hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member heterocyclic ring having one O atom; R^(8a) andR^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl, hydroxy,C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R^(8a) andR^(8b) together with the carbon atom to which they are attached form aC₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl,heteroarylalkyl, or allyl; and R²⁰ and R¹¹ are each, independently, H,C₁-C₈ alkyl, C₁-C₈ alkenyl, C,-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R¹⁰and R¹¹ together with the N atom to which they are attached form aheterocyclic ring.
 48. The salt of claim 47 wherein said salt is atartaric acid salt.
 49. The salt of claim 47 wherein said tartaric acidis L-(+)-tartaric acid.
 50. The salt of claim 47 having Formula Vb. 51.The salt of claim 47, 49, or 50 wherein R ¹ is H, R² is Me, R³is H, R⁴is Cl, R⁵ is H, R⁶ is H, R^(8a) is H, and R^(8b) is H.
 52. A compositioncomprising at least one chiral resolving acid salt of claim
 47. 53. Thecomposition of claim 52 wherein said composition comprises said tartaricacid salt form of a compound of Formula Va and said tartaric acid saltform of a compound of Formula Vb, wherein said composition is enrichedin one of either of said tartaric acid salt form of a compound ofFormula Va or said tartaric acid salt form of a compound of Formula Vb.54. A hydrochloric acid salt of a compound of Formula Va or Vb:

wherein: R¹ is H or C₁-C₈ alkyl; R² is C₁-C₈ alkyl, —CH₂—O—(C₁-C₈alkyl), C(O)O—(C₁-C₈ alkyl), —C(O)NH—(C₁-C₈ alkyl), OH, C₁-C₄ haloalkyl,or CH₂OH; R³, R⁴, R⁵, and R⁶ are each, independently, H, halo, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl,hydroxy, OR⁹, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl,hydroxyalkyl, NR¹⁰R¹¹, CN, NO₂, heterocycloalkyl, aryl, or heteroaryl,wherein said aryl and heteroaryl can be substituted with one or moresubstituents selected from C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, andalkoxy; or R⁴ and R⁵ together with the atoms to which they are attachedform a 5- or 6-member ,heterocyclic ring having one O atom; R^(8a) andR^(8b) are each, independently, H, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, alkoxyalkyl, hydroxy,C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R^(8a) andR^(8b) together with the carbon atom to which they are attached form aC₃-C₇ cycloalkyl group; R⁹ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, aralkyl, aryl, heteroaryl,heteroarylalkyl, or allyl; and R¹⁰ and R¹¹ are each, independently, H,C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R¹⁰and R¹¹ together with the N atom to which they are attached form aheterocyclic ring.
 55. The salt of claim 54 having Formula Vb.
 56. Thesalt of claim 55 wherein R¹ is H, R² is Me, R³ is H, R⁴ is Cl, R⁵ is H,R⁶ is H, R^(8a) is H, and R^(8b) is H.
 57. The salt of claim 54 havingFormula Vb wherein R¹ is H, R² is Me, R³ is H, R⁴ is Cl, R⁵ is H, R⁶ isH, R^(8a) is H, and R^(8b) is H.
 58. A composition comprising at leastone hydrochloric acid salt according to any one of claims 54 to
 57. 59.A composition comprising a salt of claim
 57. 60. A method for modulatinga 5HT_(2C) receptor comprising agonizing said receptor with an effectiveamount of said hydrochloric acid salt according to any one of claims 54to
 57. 61. A method for treating a 5-HT_(2C) receptor disordercomprising administering to a patient in need of such treatment atherapeutically effective dose of a hydrochloride salt according to anyone of claims 54 to
 57. 62. A method for treating obesity comprisingadministering to a patient in need of such treatment a therapeuticallyeffective dose of a hydrochloride salt according to any one of claims 54to
 57. 63. A method for decreasing food intake in a patient comprisingadministering to a patient in need thereof a therapeutically effectivedose of a hydrochloride salt according to any one of claims 54 to 57.64. A method for inducing satiety in a patient comprising administeringto a patient in need thereof a therapeutically effective dose of ahydrochloride salt according to any one of claims 54 to
 57. 65. A methodfor controlling weight gain in a patient comprising administering to apatient in need thereof a therapeutically effective dose of ahydrochloride salt according to any one of claims 54 to 57.